Anoikis-apoptotic cell death triggered by loss of extracellular matrix (ECM) contacts is disregulated in many chronic debilitating and fatal diseases. In the autoimmune mucocutaneous diseases of pemphigus and pemphigoid excessive anoikis in the form of acantholysis or cell death by loss of cell-cell and cell-matrix contacts is the hallmark of these oral and skin lesions. In contrast, anoikis resistance contributes to cancer development and progression, and in oral squamous cell carcinoma (OSCC) anoikis resistance induces more aggressive tumors. Thus, regulating crosstalk between anoikis and survival signaling pathways is crucial to regulating tissue processes and mitigating diseases like autoimmune diseases and cancer. We recently reported that anoikis activates a CD95/Fas-mediated signaling pathway regulated by receptor-interacting protein (RIP), a kinase that shuttles between Fas-mediated cell death and integrin/FAK-mediated survival pathways in a variety of cell systems. Low RIP expression in OSCC compared to high expression levels in normal tissues underscored that RIP is at the crossroads of life and death pathways. However, it is not known how the ECM specifically interacts with the Fas receptor to mediate this mechanism and crosstalk, nor is it known how this is specifically regulated in vivo. Our preliminary data suggest that specific domains within the ECM protein fibronectin interact with the Fas receptor as the basis for this anoikis regulation. In addition, a Fas receptor mutation, which results in an inability of Fas to bind it's ligand, renders cells anoikis resistant in our system, further supporting a connection between the Fas receptor and specific domains of fibronectin. The fact that this Fas receptor mutation manifests as an autoimmune syndrome in humans (Canale-Smith syndrome) reaffirms the importance of apoptotic disregulation in autoimmune diseases. Since, there have been no reports of death receptors, like Fas interacting with ECM proteins, this constitutes a completely new area of investigation. On the survival side of the equation, we further found that sirtuins, a novel family of NAD- dependent deacetylases recently discovered to be involved in prolonging longevity and in cancer progression and metastasis, confer a survival advantage to OSCC cells. Thus, sirtuins may be important in promoting anoikis resistance in cells. Our global hypothesis is that disregulation of anoikis mediated by Fas- fibronectin interactions is central to many disease processes. Our specific hypothesis is that there are direct Fas-fibronectin interactions that mediate crosstalk with integrins to regulate anoikis via downstream signaling to RIP. Furthermore, anoikis resistant cells bypass this signaling pathway and favor sirtuin signaling to support their survival and a more aggressive phenotype in vivo. Knowledge gained from these investigations will help decipher novel interactions between matrix proteins and cell death receptors, and expand our understanding of life and death signaling networks. These data may help identify critical therapeutic targets for diseases like autoimmune diseases and oral cancer.